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| United States Patent |
6,143,767
|
|
Koike
, et al.
|
November 7, 2000
|
Piperidinylamino tricyclic compounds as substance P antagonists
Abstract
This invention provides a compound of the formula:
##STR1##
and its pharmaceutically acceptable salts, wherein Ar.sup.1 is selected
from the group having the formulae:
##STR2##
wherein, R.sup.1 and R.sup.2 are independently hydrogen or C.sub.1
-C.sub.6 alkyl;
W is (CH.sub.2).sub.a wherein n is from 1 to 3, or --CH.dbd.CH--;
X is C.sub.1 -C.sub.6 alkoxy or halo C.sub.1 -C.sub.6 alkoxy; and
Ar.sup.2 is phenyl optionally substituted by halogen atom.
These compounds are useful in the treatment of a gastrointestinal disorder,
a central nervous system (CNS) disorder, an inflammatory disease, emesis,
urinary incontinence, pain, migraine, sunburn, angiogenesis, diseases,
disorders and adverse conditions caused by Helicobacter pylori, or the
like in a mammalian subject, especially humans.
| Inventors:
|
Koike; Hiroki (New York, NY);
Wakabayashi; Hiroaki (New York, NY)
|
| Assignee:
|
Pfizer Inc (New York, NY)
|
| Appl. No.:
|
351011 |
| Filed:
|
July 12, 1999 |
Foreign Application Priority Data
| Aug 14, 1996[WO] | PCT/IB96/00798 |
| Current U.S. Class: |
514/322; 546/199 |
| Intern'l Class: |
C07D 401/04; A61K 031/454; A61K 031/454.5 |
| Field of Search: |
546/199
514/322
|
References Cited
| Foreign Patent Documents |
| 9300331 | Jan., 1993 | WO.
| |
| 9301170 | Jan., 1993 | WO.
| |
| 9404496 | Mar., 1994 | WO.
| |
| 9508549 | Mar., 1995 | WO.
| |
| 9703066 | Jan., 1997 | WO.
| |
| 9708144 | Mar., 1997 | WO.
| |
Primary Examiner: Rotman; Alan L.
Attorney, Agent or Firm: Richardson; Peter C., Ginsburg; Paul H., Waldron; Roy F.
Parent Case Text
This application is a divisional application of Ser. No. 08/907,374 filed
Aug. 7, 1997, now U.S. Pat. No. 5,972,930, which is the U.S. national
stage Section 371 of International application No. PCT/IB96/00798, filed
Aug. 14, 1996.
Claims
What is claimed is:
1. A compound of the formula (I):
##STR11##
or a pharmaceutically acceptable acid addition salt thereof, wherein
Ar.sup.1 is selected from the group having the formulae:
##STR12##
wherein, R.sup.1 and R.sup.2 are independently hydrogen or C.sub.1
-C.sub.6 alkyl;
W is (CH.sub.2), wherein n is from 1 to 3, or --CH.dbd.CH--;
X is C.sub.1 -C.sub.6 alkoxy or halo C.sub.1 -C.sub.6 alkoxy; and
Ar.sup.2 is phenyl optionally substituted by a halogen atom.
2. A compound according to claim 1, wherein X is methoxy; and Ar.sup.2 is
phenyl.
3. A compound according to claim 2, wherein n is 2 or 3.
4. A compound according to claim 3 which is
(2S,3S)-3-[7-methoxy-1,2,3,4-tetrahydroimidazo[1,2a]quinolin-8-yl)methyl]am
ino-2-phenylpiperidine or a pharmaceutically acceptable acid addition salt
thereof.
5. A pharmaceutical composition for the treatment of a medical condition
for which antagonist activity toward substance P is needed, in a mammalian
subject, which comprises a therapeutically effective amount of a compound
according to claim 1 or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
6. A pharmaceutical composition according to claim 5, wherein the medical
condition is selected from allergic disorders, angiogenesis,
gastrointestinal disorders, central nervous system disorders, inflammatory
diseases, emesis, urinary incontinence, pain, migraine, sunburn, and
diseases, disorders and adverse conditions caused by Helicobacter pylori
in a mammalian subject.
7. A method for the prevention or the treatment of a medical condition for
which antagonist activity toward substance P is needed, in a mammalian
subject, which comprises administering to said subject a therapeutically
effective amount of a compound according to claim 1 or a pharmaceutically
acceptable salt thereof.
8. A method according to claim 7, wherein the medical condition is selected
from allergic disorders, angiogenesis, gastrointestinal disorders, central
nervous system disorders, inflammatory diseases, emesis, urinary
incontinence, pain, migraine, sunburn, and diseases, disorders and adverse
conditions caused by Helicobacter pylori in a mammalian subject.
Description
TECHNICAL FIELD
This invention relates to novel piperidinylamino tricyclic compounds and
their pharmaceutically acceptable salts, and to pharmaceutical
compositions containing them. The pharmaceutically active compounds of
this invention can be used as substance P antagonists.
BACKGROUND ART
Substance P is a naturally occurring undecapeptide belonging to the
tachykinin family of peptides, the latter being so-named because of their
prompt stimulatory action on smooth muscle tissue. More specifically,
substance P is a pharmaceutically active neuropeptide that is produced in
mammals (having originally been isolated from gut) and possesses a
characteristic amino acid sequence that is illustrated by D. F. Veber et
al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and
other tachykinins in the pathophysiology of numerous diseases has been
amply demonstrated in the art. For instance, substance P has recently been
shown to be involved in the transmission of pain or migraine, as well as
in central nervous system disorders such as anxiety and schizophrenia, in
respiratory and inflammatory diseases such as asthma and rheumatoid
arthritis, respectively, and in gastrointestinal disorders and diseases of
GI tract, like ulcerative colitis and Crohn's diseases, etc. It is also
reported that the tachykinin antagonists are useful for the treatment of
allergic conditions, immunoregulation, vasodilation, bronchospasm, reflex
or neuronal control of the viscera and senile dementia of the Alzheimer
type, emesis, sunburn and Helicobacter pylori infection.
International Publications WO 93/01170, WO 95/08549 and WO 97/08144
disclose a wide variety of piperidine derivatives, as tachykinin
antagonists such as substance P antagonists.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides piperidinylamino tricyclic compounds of the
following chemical formula (I):
##STR3##
its pharmaceutically acceptable salts, wherein Ar.sup.1 is selected from
groups of the following formulae:
##STR4##
wherein, R.sup.1 and R.sup.2 are independently hydrogen or C.sub.1
-C.sub.6 (preferably C.sub.1 -C.sub.3) alkyl;
W is (CH.sub.2).sub.a wherein n is from 1 to 3, or --CH.dbd.CH--;
X is C.sub.1 -C.sub.6 (preferably C.sub.1 -C.sub.3) alkoxy or halo C.sub.1
-C.sub.6 (preferably Cl-C.sub.3) alkoxy; and
Ar.sup.2 is phenyl optionally substituted by halogen atom.
These compounds are useful as substance P antagonists, and thus useful as
analgesics or anti-inflammatory agents, or in the treatment of allergic
disorders, angiogenesis, central nervous system (CNS) disorders, emesis,
gastrointestinal disorders, sunburn, urinary incontinence, and diseases,
disorders and adverse conditions caused by Helicobacter pylori, or the
like, in a mammalian subject, especially human. These compounds are
especially useful for the treatment of CNS disorders.
Accordingly, the present invention provides a pharmaceutical composition
for the prevention or treatment of a medical condition for which
antagonist activity toward substance P is needed, in a mammalian subject,
which comprises the compound of the formula (I) or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier. The
medical condition includes allergic disorders, angiogenesis,
gastrointestinal disorders, CNS disorders, inflammatory diseases, emesis,
urinary incontinence, pain, migraine, sunburn, and diseases, disorders and
adverse conditions caused by Helicobacter pylori in a mammalian subject.
The present invention also provides a method for the prevention or
treatment of a medical condition for which antagonist activity toward
substance P is needed, in a mammalian subject, which comprises
administering to said subject a compound of the formula (I) or a
pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
In this specification, the term "C.sub.1 -C.sub.6 alkoxy" is used herein to
mean a straight or branched --OR (R is C.sub.1 -C.sub.6 alkyl) including,
but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,
isobutoxy, tert-butoxy and the like.
The term "halogen atom" is used herein to mean F, Cl, Br and I.
The term "halo C.sub.1 -C.sub.6 alkoxy" is used herein to mean a C.sub.1
-C.sub.6 alkoxy radical substituted with one or more halogen atoms
including, but not limited to, difluoromethoxy, trifluoromethoxy,
2,2,2-trifluoroethoxy and the like.
In the preferable embodiment of the present invention, X is methoxy,
Ar.sup.2 is phenyl and n is 2 or 3.
In these compounds, preferable stereochemistry of 2-Ar.sup.2 and
3-NH--CH.sub.2 --Ar.sup.1 is (2S, 3S).
Preferred individual compounds of this invention are the following:
(2S,3S)-3-[(7-methoxy-4,5-dihydro-[1,2,3,4]tetrazolo[1,5-a]quinolin-8-yl)me
thyl]amino-2-phenylpiperidine or its salts;
(2S,3S)-3-[(9-methoxy-6,7-dihydro-5H-[1,2,3,4]tetrazolo[5,1-a][2]benzazepin
-10-yl)methyl]amino-2-phenylpiperidine or its salts; and
(2S,3S)-3-[(7-methoxy-1,2,4,5-tetrahydroimidazo[1,2-a]quinolin-8-yl)
methyl]amino-2-phenylpiperidine or its salts.
General Synthesis
The piperidine compounds of the formula (I) of this invention may be
prepared as described in the following reaction schemes.
Unless otherwise indicated, in the reaction schemes that follow, Ar.sup.1,
Ar.sup.2, X and n are defined as above.
Scheme 1 illustrates the preparation of compounds of the formula (I).
##STR5##
Referring to Scheme 1, N-protection of a compound of the formula (IX)
(Ar.sup.2 is phenyl or the like and Y is for example 2-methoxyphenyl) may
be carried out by treatment with (t-BuOCO).sub.2 O (Boc.sub.2 O) in the
presence of a base such as sodium bicarbonate (NaHCO.sub.3) or
triethylamine (Et.sub.3 N) to obtain a compound of the formula (X). An
alternative route for N-protection of a compound of the formula (IX) may
be carried out by treatment with carbobenzoxy chloride (Cbz--Cl) in the
presence of a base such as sodium bicarbonate (NaHCO.sub.3) or
triethylamine (Et.sub.3 N). Compound (IX) is known or can be prepared by
known methods, for example according to a method described in
International Publication No. WO93/01170. Compound (X) is subjected to
hydrogenolysis to obtain a compound of the formula (XI). The
hydrogenolysis may be carried out by treatment with H.sub.2 or ammonium
formate (HCO.sub.2 NH.sub.4) in the presence of a metal catalyst such as a
palladium on charcoal (e.g., 20% palladium on charcoal) in a suitable
solvent.
Then, the compound (XI) is subjected to reductive alkylation with Ar.sup.1
--CHO, selected from the groups of the formulae (W, X, R.sup.1 and R.sup.2
are defined above):
##STR6##
to obtain a compound of the formula (XII). This reaction can be carried
out in the presence of hydride reagents include borohydrides such as
sodium borohydride (NaBH.sub.4), sodium cyanoborohydride (NaBH.sub.3 CN)
and sodium triacetoxyborohydride (NaB(OAc).sub.3 H), borans,
aluminum-based reagents and trialkylsilanes. Suitable solvents include
polar solvents such as methanol, ethanol, methylene chloride,
tetrahydrofuran (THF), dioxane and ethylacetate. This reaction is
typically carried out at a temperature from -78.degree. C. to reflux
temperature of the solvent, preferably 0.degree. C. to 25.degree. C. for 5
minutes to 48 hours. The compound (XII) may be converted into a compound
of the formula (I) by treatment with acid catalyst such as hydrochloride
(HCl) in methanol, concentrated (conc.) HCl in ethylacetate or CF.sub.3
CO.sub.2 H in dichloroethan under suitable conditions.
Further, compound, Ar.sup.1 --CHO as mentioned above can be prepared by
direct or indirect formylation of a corresponding tetrazole compound
(III-a) or (III-b) or a imidazole compound (III-c) as shown below.
Any formylation methods known to those skilled in the art may be used to
introduce a formyl group into a benzene ring. For example, direct
formylation may be accomplished by contacting the quinoline or benzazepin
compound with a suitable formylating agent in the presence of a suitable
catalyst. Suitable formylating agent/catalyst systems include
dichloromethyl methyl ether/titanium (IV) chloride (Cl.sub.2 CHOCH.sub.3
/TiCl.sub.4), trifluoroacetic acid (CF.sub.3 CO.sub.2
H)/hexamethylenetetamine (modified Duffs conditions) and phosphoryl
trichloride (POCl.sub.3)/DMF (Vilsmeier's conditions). Indirect
formylation may be achieved by halogenating the quinoline or benzoazepin
compound, displacing the halogen atom introduced with a cyano group, and
then subjecting the resultant cyano-substituted compound to reduction. The
halogenation as used herein may be carried out according to the procedure
reported in G. A. Olah et al. J. Org Chem, Vol. 58, p. 3194, 1993. The
displacement of the halogen atom with a cyano group may be performed
according to the methods reported in D. M. Tschaem et al., Synth Commun,
Vol. 24., p. 887, 1994 or K. Takagi et al., Bull Chem. Soc. Jpn. Vol. 64,
p. 1118, 1991. The reduction as used herein may be performed in the
presence of diisopropyl aluminiumhydride (DIBAL-H) in dichloromethane or
Raney nickel in formic acid.
Scheme 2 illustrates methods for preparing a compound of the formula
(III-a), (III-b) or (III-c).
##STR7##
A tetrazole compound (III-a) or (III-b) can be prepared by reacting a
corresponding compound of the formula (V), such as 1-indanone or
1-tetralone derivative, with sodium azide or potassium azide in the
presence of an acid catalyst such as sulfonic acid (Route 1). This
reaction can be carried out for example in a reaction inert solvent such
as dichloromethane, at a temperature from -50.degree. C. to reflux
temperature of the solvent , preferably from 0.degree. C. to 25.degree. C.
for 10 minutes to 48 hours, preferably 30 minutes to 3 hours.
Alternatively, the tetrazole compound (III-a) or (III-b) can be prepared
from a compound (IV-a) or (IV-b) with POX.sub.3 (X is Cl or Br) alone or
in the presence of PX.sub.5, and further reaction of the reaction mixture
with sodium azide or potassium azide to give the compound (III-a) or
(III-b) (Route 2-2, reported for example in Japanese Unexamined Patent
Publication Gazette No. 52-57195). The compound of (IV-a) or (IV-b) can be
reacted with Lawesson's Reagent in a reaction inert solvent, such as
toluene, at reflux temperature for 5 minutes to 24 hours to exchange oxo
group of the compound (IV-a) or (IV-b) with thioxo group. Then the thioxo
compound can be reacted with hydrazine, preferably in a poler solvent,
such as water, methanol or ethanol at a temperature from 0.degree. C. to
100.degree. C. for 5 minutes to 24 hours, followed by a reaction with
nitrous acid for example in water in the presence of acid such as acetic
acid at a temperature from -15.degree. C. to 15.degree. C. for 5 minutes
to 24 hours to give the compound of (III-a) or (III-b).
The intermediate (IV-a) or (IV-b) may also be reacted with diethyl
azodicarboxylate (DEAD) in the presence of triphenylphosphine (Ph.sub.3 P)
in a reaction inert solvent such as azidotrimethylsilane (TMSN.sub.3) to
give the compound of (III-a) or (III-b) (J. V. Duncia et al., J. Org.
Chem. 1991, Vol. 56, pp. 2395-2400).
The compound (IV-a) or (IV-b) can be prepared by subjecting a compound (V)
to the Schmidt reaction (Route 2-1, reported in for example March's
Advanced Org. Chem., p. 986-987). The Schmidt reaction can be carried out
at a temperature from -50.degree. C. to reflux temperature of the solvent
for 10 minutes to 48 hours.
The intermediate of the formula (IV-a), wherein n is 2, may be prepared by
reacting a nitrobenzaldehyde (VIII) with malonic acid in the presence of
pyridine in a reaction inert solvent such as ethanol to give a compound
(VII) (Route 4-1), followed by a conventional hydrogenation, for example,
using a metal catalyst such as a palladium on charcoal (Route 4-2) (G. H.
Jones et. al., Journal of Medicinal Chemistry, Vol. 30, No.2, pp. 295-303,
1987). The reaction of the compound (VIII) with malonic acid in the
presence of pyridine can be carried out by heating the mixture at the
solvent reflux temperature for 30 minutes to 3 days. Then, the
intermediate (IV-a) can be reacted with a corresponding ethylenediamine in
the presence of toluene-p-sulfonic acid (p-TsOH) to give the compound
(III-c) (Route 3-1) according to the methods reported in R. F. Cookson et
al., J. S. C. Perkin I, p. 1850, 1975. This reaction is typically carried
out without solvent or in a reaction inert solvent such as xylene at a
temperature of 100.degree. C. to 250.degree. C. for 30 minutes to 48
hours. The compound of formula (III-c) can be oxidized to give a compound
of (III-d) (Route 3-2) under suitable conditions known to a skilled
person. This reaction can be carried out in the presence of a metal
catalyst such as Raney nickel in a reaction inert solvent such as methanol
or ethanol, or in the presence of an oxidizing agent such as KMnO.sub.4 or
MnO.sub.2 in a reaction inert solvent such as acetone, benzene or toluene.
Starting materials of the formula (V) and (VIII) are either known, or may
be prepared according to conventional procedures known for the preparation
of analogous compounds.
The compounds of formula (I), and the intermediates shown in the above
reaction schemes can be isolated and purified by conventional procedures,
such as recrystallization or chromatographic separation.
As the piperidine compounds of this invention possess at least two
asymmetric centers, they are capable of occurring in various
stereoisomeric forms or configurations. Hence, the compounds can exist in
separated (+)- and (-)-optically active forms, as well as mixtures
thereof. The present invention includes all such forms within its scope.
Individual isomers can be obtained by known methods, such as optical
resolution, optically selective reaction, or chromatographic separation in
the preparation of the final product or its intermediate.
In so far as the piperidine compounds of this invention are basic
compounds, they are all capable of forming a wide variety of different
salts with various inorganic and organic acids. Although such salts must
be pharmaceutically acceptable for administration to animals, it is often
desirable in practice to initially isolate the piperidine base compound
from the reaction mixture as a pharmaceutically unacceptable salt and then
simply convert to the free base compound by treatment with an line reagent
and thereafter convert the free base to a pharmaceutically acceptable acid
addition salt. The acid addition salts of the piperidine base compounds of
this invention are readily prepared by treating the base compound with a
substantially equivalent amount of the chosen mineral or organic acid in
an aqueous solvent or in a suitable organic solvent, such as methanol or
ethanol. Upon careful evaporation of the solvent, the desired solid salt
is readily obtained. The acid which are used to prepare the
pharmaceutically acceptable acid addition salts of the aforementioned
piperidine base compounds of this invention are those which form non-toxic
acid addition salts, i.e., salts containing pharmaceutically acceptable
anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,
sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate,
citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate,
fumarate, gluconate, saccharate, benzoate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate))salts.
The piperidine compounds of the invention which have also acidic groups are
capable of forming base salts with various pharmaceutically acceptable
cations. Examples of such salts include the alkali metal or alkaline-earth
metal salts and particularly, the sodium and potassium salts. These salts
are all prepared by conventional techniques.
The chemical bases which are used as reagents to prepare the
pharmaceutically acceptable base salts of this invention are those which
form non-toxic base salts with the herein described acidic piperidine
derivatives. These particular non-toxic base salts include those derived
form such pharmaceutically acceptable cations as sodium, potassium,
calcium and magnesium, etc. These salts can easily be prepared by treating
the aforementioned acidic piperidine compounds with an aqueous solution
containing the desired pharmaceutically acceptable cation, and then
evaporating the resulting solution to dryness, preferably under reduced
pressure. Alternatively, they may also be prepared by mixing lower
alkanoic solutions of the acidic compounds and the desired alkali metal
alkoxide together, and then evaporating the resulting solution to dryness
in the same manner as before. In either case, stoichiometric quantities of
reagents are preferably employed in order to ensure completeness of
reaction and maximum production of yields of the desired final product.
The active piperidine compounds of the present invention exhibit
significant substance P receptor-binding activity and therefore, are of
value in the treatment of a wide variety of clinical conditions which are
characterized by the presence of an excess of said substance P activity.
Such conditions include gastrointestinal disorders, central nervous system
disorders, inflammatory diseases, emesis, urinary incontinence, pain,
migraine or angiogenesis in a mammalian subject, especially humans. For
treatment of emesis, these compounds may preferably be used in combination
with a 5HT.sub.3 receptor antagonist.
The active piperidine compounds of the formula (I) of this invention can be
administered via either the oral, parenteral or topical routes to mammals.
In general, these compounds are most desirably administered to humans in
doses ranging from about 0.3 mg up to 750 mg per day, although variations
will necessarily occur depending upon the weight and condition of the
subject being treated and the particular route of administration chosen.
However, a dosage level that is in the range of from about 0.06 mg to
about 2 mg per kg of body weight per day is most desirably employed.
Nevertheless, variations may still occur depending upon the species of
animal being treated and its individual response to said medicament, as
well as on the type of pharmaceutical formulation chosen and the time
period and interval at which such administration is carried out. In some
instances, dosage levels below the lower limit of the aforesaid range may
be more than adequate, while in other cases still larger doses may be
employed without causing any harmful side effects provided that such
higher dose levels are first divided into several small doses for
administration throughout the day.
The compounds of the present invention may be administered alone or in
combination with pharmaceutically acceptable carriers or diluents by
either of the above routes previously indicated, and such administration
can be carried out in single or multiple doses. More particularly, the
novel therapeutic agents of the invention can be administered in a wide
variety of different dosage forms, i.e., they may be combined with various
pharmaceutically acceptable inert carriers in the form of tablets,
capsules, lozenges, trochees, hard candies, powders, sprays, creams,
salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous
suspensions, injectable solutions, elixirs, syrups, and the like. Such
carriers include solid diluents or fillers, sterile aqueous media and
various nontoxic organic solvents, etc. Moreover, oral pharmaceutical
compositions can be suitably sweetened and/or flavored. In general, the
therapeutically-effective compounds of this invention are present in such
dosage forms at concentration levels ranging about 5.0% to about 70% by
weight.
For oral administration, tablets containing various excipient such as
microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium
phosphate and glycine may be employed along with various disintegrants
such as starch and preferably corn, potato or tapioca starch, alginic acid
and certain complex silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl sulfate and
talc are often very useful for tabletting purposes. Solid compositions of
a similar type may also be employed as fillers in gelatine capsules;
preferred materials in this connection also include lactose or milk sugar
as well as high molecular weight polyethylene grycols. When aqueous
suspensions and/or elixirs are desired for oral administration, the active
ingredient may be combined with various sweetening or flavoring agents,
coloring matter or dyes, and, if so desired, emulsifying and/or suspending
agents as well, together with such diluents as water, ethanol, propylene
glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present
invention in either sesame or peanut oil or in aqueous propylene glycol
may be employed. The aqueous solutions should be suitably buffered
(preferably pH>8) if necessary and the liquid diluent first rendered
isotonic. These aqueous solutions are suitable for intravenous injection
purposes. The oily solutions are suitable for intra-articular,
intra-muscular and subcutaneous injection purposes. The preparation of all
these solutions under sterile conditions is readily accomplished by
standard pharmaceutical techniques well-known to those skilled in the art.
Additionally, it is also possible to administer the compounds of the
present invention topically when treating inflammatory conditions of the
skin and this may preferably be done by way of creams, jellies, gels,
pastes, ointments and the like, in accordance with standard pharmaceutical
practice.
The activity of the compounds of the present invention, as substance P
antagonists, is determined by their ability to inhibit the binding of
substance P at its receptor sites in CHO-cells which reveal NK1 receptor
or IM-9 cells employing radioactive reagents. The substance P antagonist
activity of the herein described piperidine compounds is evaluated by
using the standard assay procedure described by D. G. Payan et al., as
reported in The Journal of Immunology, Vol. 133, p. 3260, 1984. This
method essentially involves determining the concentration of the
individual compound required to reduce by 50% the amount of radiolabelled
substance P reagents at their receptor sites in said isolated cow tissues
or IM-9 cells, thereby affording characteristic IC.sub.50 values for each
compound tested. More specifically, inhibition of [.sup.3 H]SP binding to
human IM-9 cells by compounds are determined in assay buffer (50 mM
Tris-HCl (pH 7.4), 1 mM MnCl.sub.2, 0.02 % bovine serum albumin,
bacitracin (40 .mu.g/ml), leupeptin (4 .mu.g/ml), chymostatin (2 .mu.g/ml)
and phosphoramidon (30 .mu.g/ml)). The reaction is initiated by the
addition of cells to assay buffer containing 0.56 nM [.sup.3 H]SP and
various concentrations of compounds (total volume; 0.5 ml) and allowed to
incubate for 120 min at 4.degree. C. Incubation is terminated by
filtration onto GF/B filters (presoaked in 0.1% polyethylenimine for 2
hours). Nonspecific binding is defined as the radioactivity remaining in
the presence of 1 .mu.M SP. The filters are placed into tubes and counted
using liquid scintillation counter. Some compounds, prepared in the
working examples as described below, were tested in accordance with the
above procedures, and showed good binding activities (i.e., IC.sub.50
value of 0.1 to 50 .mu.M).
The adverse effect on Ca.sup.2+ channel binding affinity is determined by
study of verapamil binding in a rat heart membrane preparation. More
specifically, verapamil binding is performed as previously described by
Reynolds et al., (J. Phannacol. Exp. Ther. Vol. 237, p. 731, 1986).
Briefly, incubations are initiated by the addition of tissue to tubes
containing 0.25 nM [.sup.3 H]desmethoxyverapamil and various
concentrations of compounds (total volume; 1 ml). Nonspecific binding is
defined as radioligand binding remaining in the presence of 3-10 .mu.M
methoxyverapamil.
The activity of the compounds of this invention against CNS disorders is
determined in a [Sar.sup.9, Met(O.sub.2).sup.11 ]substance P-induced
tapping test in gerbils. More specifically, gerbils are lightly
anesthetized with ether and the skull surface is exposed. [Sar.sup.9,
Met(O.sub.2).sup.11 ]substance P or vehicle (5 .mu.l) are administered
directly into the lateral ventricles via a 25 gauge needle inserted 3.5 mm
below lambda. Following injection, gerbils are placed in 2 liter beaker
individually and monitored for repetitive hind paw tapping. Some compounds
prepared in the following Examples were tested in accordance with these
testing methods. As a result, it was found that the compounds of the
present inventions have good antagonist activity toward substance P,
particularly good activity against CNS disorders with favorable
metabolical properties.
The anti-inflammatory activity of the compounds of this invention is
demonstrated by a capsaicin-induced plasma extravasation test. In this
test, anti-inflammatory activity is determined as the percent inhibition
of plasma protein extravasation in the ureters of male Hartley guinea pigs
(weighing 300-350 g). Plasma extravasation is induced by intraperitoneal
injection of capsaicin (30 .mu.M in 0.1% BSA containing buffer, 10
ml/animal) into the guinea pigs pentobarbital-anesthetised 25 mg/kg i.p.)
and fasted overnight. Test compounds are dissolved in 0.1% methyl
cellulose-water and given orally 1 hour before capsaicin challenge. Evans
blue dye (30 mg/kg) is administered intravenously 5 minutes before the
challenge. The animals are killed 10 minutes after capsaicin injection and
both right and left ureter are removed. Tissue dye content is quantitated
after overnight formamide extraction at 600 nm absorbance. This test
method is known in the literature (A. Nagahisa et al., European Journal of
Pharmacology, Vol. 217, pp. 191-195, 1992).
The half life of the compounds of this invention is determined in a human
liver microsome preparation. More specifically, the compound (1 .mu.M) was
incubated with pooled human liver microsome (2.0 mg/ml), NADP (1.3 mM),
NADH (0.93 mM), glucose-6-phosphate (3.3 mM) MgCl.sub.2 (3.3 mM), and
glucose-6-phosphate dehydrogenase (8 units/ml) in a total volume of 1.2 ml
100 mM potassium phosphate buffer, pH 7.4. At various time points (0, 5,
10, 30 and 60 min), a 100 .mu.l sample was added to acetonitrile solution
(1.0 ml), which included an internal standard. The precipitated protein
was spun down in a centrifuge (3,000.times. g, 5 min). The supernatant was
analyzed by LC-MS. LC-MS unit was consisted of Hewlett Packard HP1090 HPLC
system and Sciex API-III. Samples(10 .mu.l) were injected by means of
autosampler, onto Hewlett Packard ODS-Hypersil column (2.1.times.20 mm). A
mobile phase was consisted of 80% acetonitrile in 10 mM ammonium acetate.
The measurement of API-III was analyzed with multiple reacting monitoring
(MRM) detection.
EXAMPLES
The present invention is illustrated by the following examples. However, it
should be understood that the invention is not limited to the specific
details of these examples. Melting points were taken with a Buchi micro
melting point apparatus and uncorrected. Infrared Ray absorption spectra
(IR) were measured by a Shimadzu infrared spectrometer (IR-470). .sup.1 H
nuclear magnetic resonance spectra (NMR) was measured in CDCl.sub.3 by a
JEOL NMR spectrometer (JNM-GX270, 270 MHz for .sup.1 H) unless otherwise
indicated and peak positions are expressed in parts per million (ppm)
downfield from tetramethylsilane. The peak shapes are denoted as follows:
s, singlet; d, doublet; t, triplet; m, multiplet.
Example 1
Preparation of
(2S,3S)-3-[(7-methoxy-4,5-dihydro-[1,2,3,4]tetrazolo[1,5-a]quinolin-8-yl)m
ethyl]amino-2-phenylpiperidine dihydrochloride (Compound 8)
(i) 7-Methoxy-4,5-dihydro-[1,2,3,4]tetrazolo[1,5-a]quinoline (Compound 1)
This compound was prepared according to the procedures described in
Japanese Unexamined Patent Publication Gazette No. 52-57194.
(ii)
7-Methoxy-4,5-dihydro-[1,2,3,4]tetrazolo[1,5-a]quinoline-8-carboxaldehyde
(Compound 2)
To a stirred solution of Compound 1 (160 mg, 0.79 mmol) in TFA (16 ml) was
added hexamethylenetetramine (1.1 g, 7.9 mmol), and refluxed for 3 days.
The solvent was evaporated, and the residue was diluted with AcOEt. This
organic layer was washed with water and brine, dried over MgSO.sub.4,
filtered, and concentrated. This was purified by SiO.sub.2 chromatography
to give Compound 2 (90 mg, 0.39 mmol, 50%) as a white solid.
.sup.1 H-NMR (270 MHz) .delta.(CDCl.sub.3) 10.46 (1H, s), 8.45 (1H, s),
7.03 (1H, s), 4.02 (3H, s), 3.42-3.34 (2H, m), 3.26-3.17 (2H, m) ppm.
(iii) (2S,3S)-3-(2-Methoxybenzyl)amino-2-phenylpiperidine dihydrochloride
(Compound 3)
This compound was prepared according to the procedures described in
WO93/01170.
(iv)
(2S,3S)-1-tert-Butoxycarbonyl-3-(2-methoxybenzyl)amino-2-phenylpiperidine
(Compound 4)
To a stirred and ice-cooled mixture of Compound 3 (10.0 g, 27.1 mmol), 3.0
M NaOH aq. (36.1 ml, 108.4 mmol) and tert-BuOH (15.0 ml) was added
(tert-BuOCO).sub.2 O (Boc.sub.2 O, 7.39 g, 33.8 mmol). After stirring at
room temperature overnight, the mixture was extracted with AcOEt (x3). The
combined AcOEt extracts were washed with sat. NaHCO.sub.3 and brine, dried
over Na.sub.2 SO.sub.4, and concentrated to give Compound 4 (11.3 g,
quant.) as a pale yellow syrup.
IR (film) 3350, 1693, 1605, 1590, 1492, 755 cm.sup.-1 ; .sup.1 H-NMR (270
MHz) .delta.(CDCl.sub.3) 7.58 (2H, br.d,J=7.3 Hz), 7.36-7.16 (5H, m), 6.89
(1H, ddd,J=7.5, 7.5, 1.1 Hz), 6.81 (1H, dd,J=8.4, 0.8 Hz), 5.47 (1H,
br.s), 3.96 (1H, dm,J=13.4 Hz), 3.87 (1H, d,J=13.6 Hz), 3.79 (1H, d,J=13.6
Hz), 3.70 (3H, s), 3.10-2.99 (1H, m), 2.94 (1H, dd,J=12.5, 3.4 Hz),
1.87-1.74 (2H, m), 1.74-1.40 (3H, m), 1.41 (9H, s) ppm.
This was employed in the next step without further purification.
(v) (2S,3S)-3-Amino-1-tert-butoxycarbonyl-2-phenylpiperidine (Compound 5)
A mixture of Compound 4 (11.3 g), 20% Pd(OH).sub.2 /C (Pearlman's catalyst,
3.7 g), and MeOH (90 ml) was stirred under an atmosphere of H.sub.2
(balloon) at room temperature for 4 days. The catalyst was filtered off by
the aid of celite, and washed with MeOH. The combined solvents were
concentrated to give crude Compound 5 (8.59 g, quant.).
This was dissolved in i-propanol (20 ml), and then a warmed solution of
fumaric acid (1.57 g, 13.5 mmol) in i-propanol (20 ml) was added in one
portion to this solution at room temperature. When the mixture was
scratched with a spatula, there took place precipitation of white solids
with ease. After the mixture was left to stand at 4.degree. C. in a
refrigerator overnight, the crystals precipitated were collected by
filtration, washed with ice-chilled i-propanol, and dried in vacuo at
50.degree. C. to give a first crop of
(2S,3S)-3-amino-1-(tert-butoxycarbonyl)-2-phenylpiperidine semifumarate
Compound 6 (6.14 g, 68%) as white short needles. The combined filtrate and
washing were concentrated to give a residual solid (4.56 g), which was
recrystallized from i-propanol and i-Pr.sub.2 O to give a second crop of
Compound 6 (1.25 g, 13.7%).
mp 165.7-168.8.degree. C.; Anal.% Calc for C.sub.18 H.sub.26 N.sub.2
O.sub.4.0.4H.sub.2 O: C; 63.29, H; 7.91, N; 8.20. Found: C; 63.64, H;
8.22, N; 7.79.
After a suspension of Compound 6 (1.24 g, 3.71 mmol) in H.sub.2 O was
ice-cooled, 20% NaOH aq. was added until the mixture became basic. The
mixture was then extracted with AcOEt (x3). The combined AcOEt extracts
were washed with sat. NaCl aq., dried over Na.sub.2 SO.sub.4, and
concentrated to give pure Compound 5 (0.95 g, 93.1%). IR (film) 3370,
3310, 1695, 1682, 1807, 1590, 1494, 1250, 1180, 1150, 756, 703 cm.sup.-1
.sup.1 H-NMR (270 MHz) .delta.(CDCl.sub.3) 7.47-7.39 (2H, m), 7.37-7.23
(5H, m), 5.19 (1H, br.d,J=6.2 Hz), 4.00 (1H, dm, J=13.0 Hz), 3.25-3.05
(2H, m), 1.94-1.83 (1H, m), 1.83-1.56 (4H, m), 1.36 (9H, s), 1.32 (2H,
br.s) ppm.
(vi)
(2S,3S)-1-tert-Butoxycarbonyl-3-[(7-methoxy-4,5-dihydro[1,2,3,4]tetrazolo[
1,5-a]quinolin-8-yl)methyl]amino-2-phenylpiperidine (Compound 7)
To a stirred solution of Compound 2 (65 mg, 0.28 mmol) and Compound 5 (78
mg, 0.28 mmol) in CH.sub.2 Cl.sub.2 (5 ml) was added NaB(OAc).sub.3 H (119
mg, 0.56 mmol), and stirred for 3 h. The mixture was quenched by the
addition of sat. NaHCO.sub.3, and extracted with CH.sub.2 Cl.sub.2. The
organic layers were combined, dried over MgSO.sub.4, filtered, and
concentrated. This was purified by SiO.sub.2 chromatography to give 7 (110
mg, 0.23 mmol, 82%) as a colorless oil.
.sup.1 H-NMR (270 MHz) .delta.(CDCl.sub.3) 7.90 (1H, s), 7.62-7.54 (2H, m),
7.37-7.22 (3H, m), 6.77 (1H, s), 5.51-5.43 (1H, m), 4.01-3.85 (3H, m),
3.77 (3H, s), 3.35-3.28 (2H, m), 3.16-2.95 (4H, m), 1.97-1.40 (4H, m),
1.40 (9H, s) ppm.
(vii)
(2S,3S)-3-[(7-Methoxy-4,5-dihydro-[1,2,3,4]tetrazolo[1,5-a]quinolin-8-yl)m
ethyl]amino-2-phenylpiperidine dihydrochloride (Compound 8)
To a stirred solution of Compound 7 (110 mg, 0.23 mmol) in AcOEt (6 ml) was
added an excess amount of HCl--MeOH, and stirred for 1 day. After the
solvent was evaporated, the residual solid was recrystallized from
MeOH--Et.sub.2 O. The crystals precipitated were collected by filtration,
washed with Et.sub.2 O, and dried in vacuo at 30.degree. C. to give
Compound 8 (65 mg, 0.14 mmol, 61%) as a white solid.
mp 226-228.degree. C. IR (KBr) 3425, 2935, 2665, 2590, 1628, 1559, 1503,
1449, 1331, 1244, 1150, 1042 cm.sup.-1. .sup.1 H-NMR (270 MHz)
.delta.(free base; CDCl.sub.3) 7.66 (1H, s), 7.40-7.25 (5H, m), 6.65 (1H,
s), 4.10-4.06 (1H, m), 3.71 (1H, d, J=13.9 Hz), 3.55-3.42 (2H, m), 3.52
(3H, s), 3.35-3.28 (2H, m), 3.15-2.85 (4H, m), 2.30-1.50 (4H, m) ppm.
Anal. Calc for C.sub.22 H.sub.26 N.sub.6 O.2HCl.H.sub.2 O: C, 54.89%, H,
6.28%, N, 17.46%. Found: C, 54.78%, H, 5.90%, N, 17.26%.
Example 2
Preparation of
(2S,3S)-3-[(9-methoxy-6,7-dihydro-5H-[1,2,3,4]tetrazolo[5,1-a][2]benzazepi
n-10-yl)methyl]amino-2-phenylpiperidine dihydrochloride (Compound 12)
(i) 9-Methoxy-6,7-dihydro-5H-[1,2,3,4]tetrazolo[5,1-a][2]benzazepine
(Compound 9)
To a stirred solution of 6-methoxy-1-tetralone (1.0 g, 5.7 mmol) in
CH.sub.2 Cl.sub.2 (10 ml) was added conc. H.sub.2 SO.sub.4 (5 ml) at
0.degree. C., and then NaN.sub.3 (1.0 g) was added gradually over 30 min.
The mixture was warmed up to room temperature, and stirred for 3 h. The
mixture was cooled, basified with NaOH aq., and extracted with CH.sub.2
Cl.sub.2. The organic layers were combined, dried over MgSO.sub.4,
filtered, and concentrated. This residue was purified by SiO.sub.2
chromatography to give Compound 9 (70 mg, 0.32 mmol, 5.6%) as a colorless
oil.
.sup.1 H-NMR (270 MHz) .delta.(CDCl.sub.3) 8.25 (1H, d, J=8.8 Hz), 6.94
(1H, dd, J=8.8, 2.6 Hz), 6.81 (1H, d, J=2.6 Hz), 4.61 (2H, t, J=6.6 Hz),
3.88 (3H, s), 3.02-2.93 (2H, m), 2.45-2.33 (2H, m) ppm.
(ii)
9-Methoxy-6,7-dihydro-5H-[1,2,3,4]tetrazolo[5,1-a][2]benzazepine-10-carbox
aldehyde (Compound 10)
This compound was prepared from Compound 9 in the same manner of Compound
2.
.sup.1 H-NMR (270 MHz) .delta.(CDCl.sub.3) 10.42 (1H, s), 8.75 (1H, s),
6.92 (1H, s), 4.67-4.60 (2H, m), 4.02 (3H, s), 3.10-3.03 (2H, m),
2.50-2.38 (2H, m) ppm.
(iii)
(2S,3S)-1-tert-Butoxycarbonyl-3-[(9-methoxy-6,7-dihydro-5H-[1,2,3,4]tetraz
olo[5,1-a][2]benzazepin-10-yl)methyl]amino-2-phenylpiperidine (Compound 11)
This compound was prepared from Compound 10 and Compound 5 in the same
manner of Compound 7.
.sup.1 H-NMR (270 MHz) .delta.(CDCl.sub.3) 8.16 (1H, s), 7.60-7.54 (2H, m),
7.35-7.20 (3H, m), 6.68 (1H, s), 5.48-5.40 (1H, m), 4.59 (2H, t, J=6.6
Hz), 3.98-3.75 (3H, m), 3.76 (3H, s), 3.12-2.92 (4H, m), 2.43-2.32 (2H,
m), 1.93-1.50 (4H, m), 1.40 (9H, s) ppm.
(iv)
(2S,3S)-3-[(9-Methoxy-6,7-dihydro-5H-[1,2,3,4]tetrazolo[5,1-a][2]benzazepi
n-10-yl)methyl]amino-2-phenylpiperidine dihydrochloride (Compound 12)
This compound was prepared from Compound 11 in the same manner of Compound
8.
mp 225-227.degree. C. (KBr) 3425, 2945, 2670, 2500, 1619, 1500, 1453, 1417,
1160 cm.sup.-1. .sup.1 H-NMR (270 MHz) .delta.(free base; CDCl.sub.3) 8.01
(1H, s), 7.40-7.20 (5H, m), 6.55 (1H, s), 4.70-4.50 (2H, m), 4.05-3.95
(1H, m), 3.71 (1H, d, J=13.9 Hz), 3.60-3.33 (2H, m), 3.51 (3H, s),
3.05-2.80 (4H, m), 2.47-2.30 (2H, m), 2.20-1.90 (2H, m), 1.75-1.42 (2H, m)
ppm. Anal. Calc for C.sub.23 H.sub.28 N.sub.6 O.2HCl.2H.sub.2 O: C,
53.80%, H, 6.67%, N, 16.37%. Found: C, 53.47%, H, 6.29%, N, 16.20%.
Example 3
Preparation of
(2S,3S)-3-[(7-methoxy-1,2,4,5-tetrahydroimidazo[1,2-a]quinolin-8-yl)methyl
]amino-2-phenylpiperidine trihydrochloride (Compound 17)
(i) 6-Methoxy-2-oxo-1,2,3,4-tetrahydroquinoline (Compound 13)
This compound was prepared according to the procedures described in J. Med.
Chem, 30, 295(1987).
(ii) 7-Methoxy-1,2,4,5-tetrahydroimidazo[1,2-a]quinoline (Compound 14)
To a mixture of Compound 13 (0.50 g, 2.6 mmol) and ethylenediamine (0.88
ml, 13.1 mmol) was added p-TsOH H.sub.2 O (2.5 g, 13-1 mmol), and heated
to 200.degree. C. for 24 h. The cooled mixture was solved with 6N HCl,
basified with NaOH aq., and extracted with CH.sub.2 Cl.sub.2. The organic
layers were combined, dried over MgSO.sub.4, filtered, and concentrated.
This residue was purified by SiO.sub.2 chromatography to give Compound 14
(63 mg, 0.31 mmol, 12%) as a colorless oil.
.sup.1 H-NMR (270 MHz) 6 (CDCl.sub.3) 6.80-6.58 (3H, m), 4.12-3.82 (4H, m),
3.77 (3H, s), 2.98-2.82 (4H, m) ppm.
(iii) 7-Methoxy-1,2,4,5-tetrahydroimidazo[1,2-a]quinoline-8-carboxaldehyde
(Compound 15)
To a stirred solution of Compound 14 (63 mg, 0.31 mmol) in CH.sub.2
Cl.sub.2 (5 ml) was added TiCl.sub.4 (0.17 ml, 1.6 mmol) at 0.degree. C.
After the reaction mixture was stirred for 10 minutes, Cl.sub.2 CHOMe
(0.14 ml, 1.6 mmol) was added at 0.degree. C., and stirred for 3 h. The
mixture was quenched by the addition of water, basified with NaOH aq., and
extracted with CH.sub.2 Cl.sub.2. The combined CH.sub.2 Cl.sub.2 extracts
were dried over MgSO.sub.4, filtered, and concentrated. The residue was
purified by SiO.sub.2 chromatography to give Compound 15 (25 mg, 35%) as a
slight yellow solid.
.sup.1 H-NMR (270 MHz) .delta.(CDCl.sub.3) 10.42 (1H, s), 7.02 (1H, s),
6.85 (1H, s), 4.05-3.90 (2H, m), 3.91 (3H, s), 3.82-3.70 (2H, m),
3.00-2.92 (2H, m), 2.78-2.70 (2H, m) ppm.
(iv) (2S,3S)-1-tert-Butoxycarbonyl-3-[(7-methoxy-
1,2,4,5-tetrahydroimidazo[1,2-a]quinolin-8-yl)methyl]amino-2-phenylpiperid
ine (Compound 16)
This compound was prepared from Compound 15 and Compound 5 in the same
manner of Compound 7.
.sup.1 H-NMR (270 MHz) .delta.(CDCl.sub.3) 7.63-7.55 (2H, m), 7.36-7.20
(3H, m), 6.66 (1H, s), 6.61 (1H, s), 5.55-5.42 (1H, m), 4.07-3.88 (7H, m),
3.70 (3H, s), 3.08-2.78 (6H, m), 1.92-1.50 (4H, m), 1.40 (9H, s) ppm.
(v)
(2S,3S)-3-[(7-Methoxy-1,2,4,5-tetrahydroimidazo[1,2-a]quinolin-8-yl)methyl
]amino-2-phenylpiperidine trihydrochloride (Compound 17)
This compound was prepared from Compound 16 in the same manner of Compound
8.
mp 226-227.degree. C. IR(KBr) 3430, 2925, 2740, 1616, 1541, 1508, 1467,
1410, 1253 cm.sup.-1. .sup.1 H-NMR (270 MHz) .delta.(free base;
CDCl.sub.3) 7.37-7.20 (5H, m), 6.53 (1H, s), 6.28 (1H, s), 3.97-3.88 (3H,
m), 3.65-3.53 (3H, m), 3.47 (3H, s), 3.40 (1H, d, J=13.9 Hz), 3.33-3.22
(1H, m), 2.90-2.73 (4H, m), 2.68-2.60 (2H, m), 2.20-2.08 (1H, m),
2.03-1.80 (1H, m), 1.80-1.55 (1H, m) 1.50-1.38 (1H, m) ppm. Anal. Calc for
C.sub.24 H.sub.30 N.sub.4 O.3HCl.2.5H.sub.2 O: C, 52.90%, H, 7.03%, N,
10.28%. Found: C, 52.50%, H, 6.64%N, 10.03%.
The chemical structure of the compounds prepared in Examples 1 to 3 are
summarized in the following table.
TABLE
______________________________________
Example Ar.sup.1 Ar.sup.2
______________________________________
1
CSTR8##
.sub.6 H.sub.6
- 2
C.sub.6 H.sub.6
- 3
C.sub.6 H.sub.6
______________________________________
The stereochemistry of 2-Ar.sup.2 and 3-NH--CH.sub.2 -Ar.sup.1 is (2s, 3S).
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